PROJECT SUMMARY Converging evidence indicates that the presence of midlife vascular risk factors (e.g. hypertension and diabetes) accelerates brain aging and increases the risk of dementia in late life. Conversely, midlife physical activity is associated with the reduced risk of dementia in late life. The potential benefits of regular aerobic exercise on neurocognitive function have been demonstrated in older adults; however, no interventional study has investigated such effects in middle-aged adults. Therefore, the overarching goal of this project is to determine the effects of regular aerobic exercise on neurocognitive function (primary outcome) as well as brain neuronal plasticity and cerebrovascular function (secondary outcomes) in middle-aged adults with subclinical cardiovascular risk factors (i.e. prehypertension and prediabetes). We will address the following aims. Aim 1: Determine the effect of regular aerobic exercise on neurocognitive function. Hypothesis: Regular aerobic exercise improves fluid cognitive performance. Aim 2: Determine the effect of regular aerobic exercise on brain plasticity. Hypothesis: Regular aerobic exercise increases prefrontal and hippocampal volumes, white matter fiber integrity in the anterior corpus callosum, and functional connectivity of the default-mode-network. Aim 3: Determine the impact of regular aerobic exercise on brain perfusion and its relation to neurocognitive function and brain plasticity. Hypotheses: 1) Regular aerobic exercise increases regional brain perfusion while attenuating cerebral blood flow (CBF) pulsatility in the large cerebral arteries; 2) The exercise-related changes in brain perfusion and CBF pulsatility mediate changes in neurocognitive function and brain plasticity. To address our aims, we will conduct 1) a cross-sectional study which compares endurance-trained adults with sedentary subjects with subclinical cardiovascular risk factors and 2) an interventional study in which those sedentary subjects undergo a 1-year program of aerobic exercise training or stretching. Cognitive function will be assessed using the NIH Toolbox Cognitive Battery complemented with sensitive neuropsychological testing on attention-executive function, episodic and working memory, and processing speed. Neuroimaging biomarkers of brain structure and function will be acquired by MRI. Brain perfusion and CBF pulsatility will be measured by arterial spin labeling, 2D time-resolved phase- contrast MRI, and transcranial Doppler. Successful accomplishment of this project will provide the urgently needed knowledge whether regular aerobic exercise improves neurocognitive function in middle-aged individuals who have high risks of developing cognitive decline and dementia in late life.